The efficacy of bevacizumab in combination with chemotherapy in ovarian cancer as first-line treatment is addressed by two phase III trials which were published in the New England Journal of Medicine in December 2011.
is a double-blind, placebo-controlled, phase 3 trial, in which 1873 patients with newly diagnosed stage III (incompletely resectable) or stage IV epithelial ovarian cancer who had undergone debulking surgery were randomly assigned to receive one of three treatments: 1. Control arm- standard chemotherapy consisting of 3-weekly intravenous paclitaxel (175 mg/m2) plus carboplatin (AUC 6) cycles 1-6 with 3-weekly placebo cycle 2-22; 2. Bevacizumab-initiation treatment- standard chemotherapy with bevacizumab (15 mg/kg) 3-weekly added in cycles 2 through 6 and placebo added in cycles 7-22; 3. Bevacizumab-throughout treatment- standard chemotherapy with bevacizumab 3-weekly for cycles 2- 22.
In the International Collaborative Ovarian Neoplasm (ICON) 7 trial2, 1528 patients were randomly assigned to either standard chemotherapy consisting of 3-weekly carboplatin (AUC 5 or 6) plus paclitaxel (175 mg/m2) cycles 1-6 or this regimen plus 3-weekly bevacizumab (7.5 mg/kg) administered concurrently for 5 or 6 cycles and continued for 12 additional cycles or until disease progression.
In the GOG-0218 study, all patients enrolled had advanced disease; 40% of patients had stage III disease with residual disease greater than 1 cm post debulking surgery and 26% with stage IV disease. In the ICON7 study, 26% had residual disease more than 1 cm, 9% had high-risk early stage ovarian cancer and 30% were at high risk for progression (FIGO stage IV or III and >1cm residual disease).
For both studies, the addition of bevacizumab increased progression-free survival. In the GOG-0218 trial, (median follow-up 17.4 months) the median progression-free survival was 10.3 months in the control group, 11.2 in the bevacizumab-initiation group, and 14.1 in the bevacizumab-throughout group (Hazard Ratio (HR) 0.717 95% CI, 0.625 to 0.824; P<0.001). In the ICON7 trial, the PFS at 36 months was 20.3 months in the standard arm compared to 21.8 months with the addition of bevacizumab (0.81; 95% CI 0.70 to 0.94; P = 0.004). The updated analyses of ICON7 suggest that the benefit of bevacizumab is greater in patients considered high risk of progression: PFS at 42 months of 14.5 months with standard therapy alone and 18.1 months with the addition of bevacizumab. The 3.6 month improvement in PFS seen in the high-risk subgroup of the ICON7 study is similar to the difference reported in GOG-0218. Furthermore, an improvement in overall survival with bevacizumab in this high-risk group (28.8 months vs 36.6 months, HR 0.64, 95% CI 0.48-0.85; p=0.002) was seen in ICON7.
Hypertension >grade 2 was significantly higher in the bevacizumab containing arms: GOG0218- control arm 7.2%, bevacizumab-initiation 16.5% and bevacizumab-throughout 22.9%; ICON7- 18% vs 2%. The number of patients reported to have gastrointestinal events including perforations was higher in the bevacizumab arms in both trials (ICON7 10 vs 3 perforations; GOG-218 7 control vs 16 bevacizumab-throughout arm grade 2 GI events).
Based on the results of the GOG-0218 and ICON7 trials, bevacizumab was recently approved by the European Commission for first-line use in advanced ovarian cancer.
Several important questions remain to be addressed in order to realise the full potential of bevacizumab for patients with ovarian cancer. Should bevacizumab maintenance be extended until disease progression? What is the best dose? Can biomarkers identify subgroups more likely to derive benefit? Should bevacizumab be used for recurrent disease based on OCEANS study3? Importantly, is the extent of benefit sufficient to justify the cost?1. Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med;365:2473-83, 2011